Stability is an important aspect of all forms of controlled release dosage forms and other formulations for active ingredients. Stability study requirements are covered in the United States Pharmacopia 24th Edition (USP XXIV), in the Good Manufacturing Practices (GMP) as well as in FDA Guidelines. The ingredients used in controlled release dosage forms often present special problems with regard to their physical stability during storage. Strategies used in the prior art to stabilize controlled release formulations include: insuring the individual ingredients are in a stable form prior to their incorporation into the product; retarding the instability by adding additional ingredients; inducing the individual ingredients to reach a stable state before the product is completed; changing the porosity and/or hydration level of a polymeric film to adjust the moisture content of the product; and proper packaging of the product.
In some instances, active ingredients of solid controlled release formulation degrade by hydrolysis. For example, hydrolysis of bupropion hydrochloride is encouraged in environments where the pH is above 4, as well as in the presence of (hydrophilic) excipients. The prior art shows that hydrolysis of certain active ingredients can be retarded in an acidic environment. Accordingly, acidified additives or formulations have been used to retard degradation.
Examples of prior art formulations of the drug bupropion hydrochloride demonstrate the use of acidic stabilizing ingredient to prevent degradation of the active ingredient. Bupropion hydrochloride is an aminoketone-derivative designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl) amino]-1-propanone hydrochloride and described in U.S. Pat. Nos. 5,358,970; 5,427,798; 5,731,000, 5,763,493; Re. 33,994; 3,819,706 and U.S. Pat. No. 3,885,046. It is marketed as an antidepressant and as an aid to smoking cessation. The drug is chemically unrelated to tricyclic, tetracyclic or selective serotonin-reuptake inhibitors. Noradrenergic pathways and/or dopaminergic effects appear to be the primary mechanism for antidepressant and smoking cessation actions. The dosing regimen for sustained-release bupropion is once or twice daily.
The stability of bupropion hydrochloride and other active ingredients may be affected by factors including formulation and storage conditions. Heat lability of bupropion hydrochloride formulations is known. Although bupropion hydrochloride is stable in bulk and in most simple blends, the drug is unstable in complex mixtures such as granulations or tablets.
Stability studies of mixtures with lubricants show that bupropion is stable in the presence of talc but stability is poor in the presence of magnesium stearate or stearic acid. A lubricant, such as, magnesium stearate is often added to prevent picking and sticking on a high-speed rotary press. Bupropion formulations without stabilizers lose more than 50% of active ingredient potency at six weeks of accelerated conditions.
Labeling of conventional tablets or extended-release tablets of bupropion hydrochloride indicates storage at a temperature of 15-25° C. and protection from light and moisture. Extended release tablets of bupropion should be stored in tight, light-resistant containers at a temperature of 20-25° C. (USP Pharmacopeial Forum, Vol. 26(4): July-August 2000).
The prior art describes the use of stabilizers to prevent degradation of the active ingredient. For example, the patents summarized below teach the addition of an organic or inorganic acid as a separate stabilizing ingredient for formulations of bupropion hydrochloride.
Sustained release tablet forms of bupropion are described in U.S. Pat. No. 5,427,798, comprising a sustained release tablet where controlled release is achieved by combining bupropion particles with microcrystalline cellulose and hydrogel-forming high molecular weight, high viscosity grades of hydroxypropyl methylcellulose. Stabilization of this formulation is taught by addition of cysteine hydrochloride or glycine hydrochloride.
Stabilization by acidification of the environment in which degradation occurs in pharmaceutical compositions containing bupropion is disclosed in U.S. Pat. No. 5,968,553. In this patent, the stabilizer is an inorganic acid having an aqueous solution pH of about 0.5 to 4.0 at a concentration of about 0.31% w/w. The inorganic acids are selected from the group consisting of hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid. The stabilizer constitutes from about 0.01% to about 5% of the amount of bupropion hydrochloride in the composition.
Solid bupropion formulations containing acidic stabilizers are also disclosed in U.S. Pat. No. 5,358,970 where the stabilizer has an aqueous pH of about 0.9 to 4.0 at an aqueous solution concentration of about 6% w/w and are solid or liquid at 30° C. Stabilizers used are selected from the group consisting of L-cysteine hydrochloride, glycine hydrochloride, ascorbic acid, malic acid, sodium metabisulfite, isoascorbic acid, citric acid, tartaric acid, L-cysteine dihydrochloride or their combinations.
Stabilization of the commercially available Wellbutrin® SR is achieved by acidification with L-cysteine hydrochloride.
Although the prior art teaches incorporating acidification additives to reduce the hydrolytic degradation of active ingredients, it is less desirable because: 1) it may not be suitable for pharmaceutical compositions with basic excipients and 2) it represents additional ingredients in the formulation. The need exists for a stable controlled release bupropion formulation that does not require a stabilizer and which may be used with basic excipients. Such delayed delivery dosage formulations have a practical application, and represent a valuable contribution to the medical arts. The present invention provides such compositions, and offers efficient and cost effective methods of preparation.